Increasingly molecularly oriented virology and genetic studies in this program of the last fifteen years have brought us to the point that our main theme in this revised renewal program is to use molecular techniques in virology and genetics to define a series of critical genes, at which genetic lesions in cancer cells have led to dysregulation of growth control. Our overall goal in the renewal program is to understand the normal function of these critical genes, and how their alterations leads to neoplasia or other abnormality, so that pharmacological or genetic methods to intervene can be devised and tested, to provide a basis for therapeutic intervention. Project 1 will define and characterize genes activated by proviral insertion that result in myeloid leukemia; the first gene characterized by the project is a novel member of a homebox gene subfamily. This subfamily is defined by PBX1, a gene involved in chromosome translocation resulting in human Pre B cell leukemia. Project 2 will characterize a gene expressed in embryonic hematopoietic stem cells, investigate its role in hematopoietic differentiation and function as a stem cell marker. Project 3 will identify and characterize melanoma tumor suppressor gene(s) in chromosome region 9p21 and study function in normal and malignant cells; the dual approach will involve characterization of the role of the p16 gene in familial melanoma in three kindreds and identification of another 9p21 suppressor gene, likely to have a direct role in several forms of neoplasia. project 4, a new project in this revision, aims to clone and characterize the gene involved in the lethal spotting (Is mutation, a murine, a murine disease similar to human Hirschsprung's disease; one form of Hirschsprung's disease is known to involve the RET oncogene which is involved in several familial neoplasias. Each of the projects involves cloning and characterization of genes with critical roles in growth, differentiation or neoplasia. Expression and functional studies, as well as gene mapping, for each of these cloned loci will be performed through interactions among the projects, taking maximum advantage of the cost, technology, expertise and idea-sharing promoted by the Program Project structure.